PROJECT SUMMARY Essentially no progress has been made in the past decade in developing more effective therapies for glioblastoma (GBM). Despite aggressive treatment with surgery, radiation and temozolomide, the median survival for GBM remains just over one year. While clinical studies have delineated the important cyto- reductive effects of radiation, the predominant failure pattern remains within the irradiated tumor volume. The significant morbidity associated with local progression of GBM represents a pressing unmet medical need. This project will evaluate 5 novel radio/chemo-sensitizing drugs in GBM patient-derived xenograft (PDX) models and will develop a rational framework for identifying the most promising combinations that should be taken forward into clinical testing. This framework can be divided into three sets of Aims: Aim 1: Define the spectrum of response and potential predictive biomarkers for effective sensitizers. The radio-sensitizing effects of CTEP agents will be evaluated in vitro and in vivo across an extensive panel of GBM PDX models. In combination with known mechanisms of action and pharmacodynamic measures of response identified in these studies, potential mechanistic biomarkers of response will be evaluated in subsequent in vivo studies. Ultimately, the studies in this aim will provide both an understanding of the fraction of tumors likely to respond to a specific therapy and may identify potential biomarkers that could be used to enrich a clinical trial population most likely to benefit from a specific combination strategy. Aim 2: Correlate key pharmacokinetic and pharmacodynamic markers with drug efficacy. A comprehensive understanding of drug distribution into tumor and normal tissues, and associated pharmacodynamic effects, are critical for defining which drugs to move forward into Phase I dose-seeking studies and to interpret Phase 0 surgical sampling studies. The focus of this aim is to define key parameters, such as the determinants of free- and bound-drug exposure in plasma, normal brain and brain tumor, and to relate these metrics to a dose range associated with effective radiosensitization. These studies will enable predictions from readily available human pharmacokinetic data in plasma as to whether effective radiosensitizing drug levels should be achievable in human tumors in the brain. Aim 3: Evaluate the potential for radio-sensitization of normal brain tissues. Radiation therapy can cause significant long-term neuro-cognitive defects that dramatically impair patient quality of life. If a specific radiosensitizer is known to potentiate these adverse effects, then this would critically inform the safe clinical deployment of this strategy. Thus, studies in this aim will evaluate drug/radiation interactions with respect to neurogenesis, neuro-inflammation and cognition in mouse models to provide an understanding of how radiosensitizing drug therapy may influence the therapeutic window for brain irradiation.